During the last two decades, the use of immunosuppressive drugs in transplantation have revolutionized our ability to treat transplant rejection and other immune disorders. However, the ultimate goal of transplantation tolerance has not yet been achieved. The overwhelming number of patients treated with cyclosporine A, corticosteroids, monoclonal antibodies, or other therapies must continue immunosuppressive therapy indefinitely, thus increasing the potential for infectious diseases and cancer. On rare occasions, individuals who discontinue their immunosuppressive drugs retain their transplanted tissue, suggesting that the immune system is capable of adapting to the foreign tissues in a way that leads to permanent engraftment of the organ. During the past several years, significant advances have occurred in our understanding of the activation of T cells by foreign antigens (including transplantation antigens) that has substantially enhanced our insights into T cell activation pathways and into regulatory T cell subsets that control immune responses. Thus, this new understanding of modulation and development may lead to more selective immunosuppressive drugs for future immunotherapy in transplantation and autoimmune disease. The goals of this program project grant during the previous grant period have been to better define the basis for immune recognition of allogeneic grafts and the role of individual T cell subsets. This information has been exploited to develop approaches to alter the balance of the immune system to maximize graft acceptance and to develop new immunosuppressive drugs that can be examined clinically in transplantation and autoimmune disease. We propose to continue our endeavors devoting substantial efforts to: dissection of the role of individual T cell subsets and distinct cell surface molecules engaged during graft recognition and immune regulation through the efforts of Drs. Frank Fitch and Gijs Van Seventer; to pursue studies to define the biochemical and molecular events associated with mitogenic and non-mitogenic anti-CD3 mAb therapy alone or in combination with other drugs; and to define the basis of T cell inactivation following anti-CD3 therapy as well as CD4 and CD8 subset regulation, in vitro and in vivo. These studies will use both murine add preclinical hu-SCID models in an effort to better understand the basis for anti-CD3-induced immunosuppression; and to develop and evaluate new mAbs for their immunosuppressive potential in-transplant recipients and patients with autoimmune diseases.